Mass Antibiotic Administration for Eradication of Ocular Chlamydia trachomatis

Trachoma, a chronic keratoconjunctivitis caused by the bacterium Chlamydia trachomatis, is the leading infectious cause of blindness in the world. Until the 20th century it was endemic in Europe and North America, and eye hospitals established in the 19th century were founded to treat trachoma. As living standards improved, trachoma disappeared from the developed world, but it remains endemic in poor rural communities in some 55 countries, most of them in Africa and Asia. The World Health Organization (WHO) estimates suggest that more than 100 million individuals have the disease, of whom 7.6 million have potentially blinding sequelae, and 1.3 million are blind.^{1 - 2}

In its early stages, mainly seen in children, trachoma causes few symptoms, but clinical signs may be observed in the conjunctiva of the everted upper eyelid, which takes on a roughened appearance due to the presence of subconjunctival lymphoid follicles. In older children and adults, repeated episodes of infection eventually lead to conjunctival fibrosis, which may distort the lid margin and cause the lashes to rub against the cornea (trichiasis). This ultimately causes blindness due to corneal opacity.³

In trachoma-endemic communities, C trachomatis infection is spread from eye to eye and from person to person by fingers, flies, and shared cloths or towels. Trachoma can be controlled by improvements in living standards and personal hygiene that reduce transmission or by mass treatment with antibiotics to eliminate the reservoir of infection. Until the 1990s, tetracycline ointment applied to the conjunctiva twice daily for 6 weeks was the recommended treatment, but it was difficult to persuade entire communities to adhere to this regimen.

A 1993 study in the Republic of The Gambia showed single-dose oral azithromycin was sufficient to cure ocular C trachomatis infection,⁴ an advance that enabled WHO to establish a global alliance in 1997 for the elimination of blinding trachoma by the year 2020.⁵ (“Elimination” in this context implies reduction in the prevalence of disease to the point at which it ceases to be a public health problem, not reduction in the prevalence of disease or infection to zero.) The manufacturer of azithromycin agreed to donate the drug for trachoma control in selected countries, following the example of another manufacturer that donated ivermectin for the control of river blindness due to the parasite Onchocerca volvulus. To date, 135 million doses of azithromycin have been given or pledged.⁶

The strategy for trachoma elimination is based on an approach reflected in the acronym SAFE: Surgery for the correction of trichiasis, Antibiotics for the elimination of C trachomatis infection, Facial cleanliness, and Environmental improvement to reduce transmission. Health education programs to encourage face washing and efforts to control fly populations through the provision of latrines or by insecticide spraying have had variable results.^{7 - 8} Mass treatment with azithromycin has been more consistently effective, especially in communities with a relatively low prevalence of trachoma, but infection often returns after a single round of treatment unless coverage is very high and population movement limited.^{9 - 13} For this reason, WHO recommends that at least 3 rounds of annual mass treatment should be offered to affected communities and that annual treatment should be continued until the district-wide prevalence of follicular trachoma in children aged 1 to 9 years is less than 10%.¹⁴ This recommendation is not based on strong evidence, and such a strategy may not be appropriate in all settings. In communities with a low baseline prevalence of infection a single treatment may suffice.¹⁰ In communities with a very high prevalence, mathematical models suggest that more frequent treatment may be needed.^{15 - 16}

In this issue of JAMA, Melese and colleagues¹⁷ have compared the effect of annual with twice yearly mass azithromycin treatment on the prevalence of ocular C trachomatis infection in 16 hyperendemic villages in Ethiopia and on the proportion of communities in which infection has been eradicated after 24 months. (“Eradication of infection” in this context means absence of ocular C trachomatis—a state that is mathematically implied rather than proven by their protocol because not every resident of each village was tested.) Mean village-level antibiotic coverage was 92.1% and did not significantly differ between the 2 study groups. The empirically observed results are similar to the results predicted by mathematical modeling: infection in children aged 1 to 5 years was eradicated more rapidly, and in a significantly higher proportion of communities, by twice yearly than by annual treatment.

This is an important study for 2 reasons. First, it suggests that modeling can provide valuable information to guide program managers in developing plans for trachoma control. Second, it shows that more frequently administered mass treatment can eradicate infection even from severely affected communities. The proportion of individuals infected at baseline was higher in the annually treated communities than those in the twice yearly treated communities, which probably accounts for the fact that the absolute reduction in prevalence of infection was greater in individuals in annually treated villages (36.8%) than those in the twice yearly treated villages (30.7%). However, the difference in mean baseline prevalence of infection was taken into account in the analysis.

The eradication of C trachomatis from endemic communities may not be necessary to prevent blinding trachoma, which is the objective of the WHO Alliance,¹⁸ but may be sufficient to reduce the prevalence and incidence of infection below a certain level, because the blinding sequelae only occur after repeated episodes of infection.¹⁹ But in hyperendemic communities, it is likely that the prevalence of infection will rapidly return to baseline levels unless infection is eradicated. This could be prevented by improving living standards, education, and the provision of improved water supply and sanitation, but unfortunately it may be decades before these improvements are implemented in all trachoma-endemic communities.

WHO recommends that mass treatment programs for trachoma should aim to achieve more than 80% coverage. The coverage required to eradicate infection is not known, but is likely to vary depending on the prevalence of infection at baseline. In one community in Tanzania, where the prevalence of infection was about 10% overall at baseline, 2 rounds of mass treatment (with coverage levels of >97% and >93%, respectively) appeared to eradicate infection for 5 years.²⁰ Required coverage may also depend on secular trends, because trachoma is disappearing from some regions in the absence of any intervention program.²¹ The results of Melese et al suggest that modeling will be a useful tool to estimate the number of rounds and coverage required of successive mass treatments in order to eradicate infection from a community.

Further work to validate or refine these models is required to determine the applicability of these results in settings with different transmission dynamics, population mobility, and antibiotic uptake. It will also be important to investigate the relative advantages and disadvantages that biannual treatment might have when applied in large populations. Treating entire regions twice yearly could help ensure that gains made from frequent antibiotic use are not eroded by reintroduction of infection from outside the treated area but will significantly increase the cost of antibiotics and of their distribution. Finally, studies to examine whether more frequent azithromycin use will result in the emergence of macrolide-resistant strains of C trachomatis²² or other important pathogens^{22 - 24} are urgently required, for such an outcome would more than offset any gain derived from biannual treatment. In the meantime, the findings of Melese et al¹⁷ represent an important contribution to understanding how blinding trachoma can be reduced and hopefully eliminated.